a) Field of the Invention
The invention concerns a method to treat conditions and diseases which are caused by the disturbance of synthesis of interferons (IFNs) and certain other substances (e.g., tumor necrosis factor) which damage the immune system and have a direct pathological action on cells.
b) Description of Related Art
Besides its anti-virus and anti-proliferative roles, IFN also plays a role as an immunoregulator (Immunology 25: 367, 1973; W. Stewart, Interferon System, 1979). The normal functioning of the interferon system in vivo is critical for the normal functioning of the immune system. A change in IFN synthesis can bring about a change in the immune system. In 1974 an article was published suggesting that the hyperproduction of IFN can be the main cause of the development of autoimmune disease (Nature 551: 2047, Feb. 22, 1974). IFN was found in the circulation of patients with autoimmune diseases and it was neutralized in vivo with antibody to leukocyte (alpha) IFN; healthy people do not have interferon in their blood (Annals of Allergy 35: 356, 1975).
Later it was shown that this hyperproduced alpha IFN is found not only in the circulation of patients with classic autoimmune diseases, but also in patients with HIV infection (J Infec Dis 146: 451, 1982). This alpha IFN is pH labile while normal alpha IFN is pH stable. This aberrant type of IFN may participate in the pathogenesis of AIDS where its presence is a predictive marker of AIDS progression (Cancer Res 46: 417, 1986). It was proposed to remove aberrant IFN from the circulation as a method of treatment of patients with autoimmune disease and AIDS, also considered an autoimmune disease.
Aberrant IFN can induce tumor necrosis factor (TNF) and its receptors (AIDS Research and Human Retroviruses 7: 545, 1991), which enhances virus replication (Proc Natl Acad Sci USA 86: 2365, 1989). In other words, aberrant IFN production reflects virus replication. The aberrant IFN induced by HIV has low anti-(HIV) viral activity (J Immunol 148: 422, 1992). In some stages of AIDS, its induction may help the virus survive.
Alpha IFN, mostly the aberrant type, may be the main cause of the development of autoimmune disease, but in some situations gamma IFN, and more rarely beta IFN, can also play a pathogenetic role since all of these participate in immune regulation. Every hyperproduction and chronic circulation of IFNs, especially aberrant IFNs, and other defective IFNs, have a negative influence on the function of different body systems, in particular the immune system (J of Clin Immunol and Immunopathol 43: 362, 1987; Am J of Med Sci 295: 532, 1988). The presence in AIDS patients of gamma IFN may be a marker of the intensification of the autoimmune process.
Besides being present in the circulation, IFNs have also been found in the cerebrospinal fluid in some patients with psychiatric and neurologic diseases (Acta Biol Med Germ 38: 879, 1979; Acta Neurol Scand 53: 152, 1976) and in the joint synovial fluid (Ann of Rheum Dis 42: 672, 1983) of patients with rheumatoid arthritis. Healthy people do not have interferons in the spinal or synovial fluids.
As is known, AIDS is induced by HIV. In autoimmune disease, where HIV like particles and their antibodies against them were found in the sera of humans and in animal models, it is possible that the particles are integral parts of the lymphocytes or organs. HIV and its particles are interferon inducers. Every antigen is an interferonogen; "self" cannot induce IFN. Thus, the production of IFN signals the invasion by a foreign antigen. IFN production, mostly IFN of the aberrant type, and its prolonged circulation in the body is an inseparable part of the development of autoimmune disease and triggers immunological chaos. For example, antibodies to CD4 in patients with HIV infection (Am J of Med 78: 621, 1985), can crossreact with class II antigen (Proc Natl Acad Sci USA 88: 3060, 1991) which in turn is induced by gamma IFN, or by gamma IFN in combination with TNF, and possibly by aberrant IFN, which induces TNF. In other words, aberrant IFN and TNF could be important pathological triggers of immune dysregulation in AIDS.
Besides classic AD and AIDS, there are a number of other pathological conditions in which autoantibodies play a pathogenic role. After cell (or organ) transplantation and after heart attack or stroke, certain antigens from the transplantation of cells (organs) or necrotic cells from the heart or the brain can stimulate the production of antibodies or immune lymphocytes (R. Johnson, L. Lynne and Wm. Seldin, Sem Nuc Med 19: 238, 1989; M. Leinonen, E. Linnanmaki, K. Mattile and M. S. Nieminen, et al., Microbiolo Path 9: 67, 1990; J. Montalban, A. Codin, J. Ordi, M. Vilardell, et al., Stroke 22: 750, 1991), which later participate in rejection (in the case of a transplant) or attack the cardiac and brain cells, aggravating the condition. Every antigen stimulation is accompanied by the immediate synthesis of interferon which triggers the immune process. To counter transplant rejection, antibodies to three kinds of interferons (alpha, beta, and gamma), or in some cases, gamma IFN alone, and the antigen of the transplanted cell or organ are placed in the immunosorbent column. To treat infarction or stroke, antibodies to IFNs as well as cardiac or brain antigens are placed in the immunosorbent column. Further, the present invention may be used in combination with immunosuppressive therapy necessary for treating infarction and stroke.
In addition, in human autoimmune disease certain cells express abnormally elevated levels of HLA class II antigens, which is stimulated by the disturbed production of gamma IFN and TNF (IFN 9, Academic Press 1987, p. 75). The disturbance of the synthesis of HLA class II antigen plays an important role in the pathogenesis of autoimmune disease and AIDS. The disturbance of HLA class II antigen leads to a disturbance of the presentation of antigens to T cells, T/B cooperation and the dysregulation of the interaction between T cells. For the normalization of the immune system, it is necessary to remove hyperproduced class II antigens, and in some cases, it is also necessary to remove its receptors. For this reason, the present invention includes in the immunosorbent antibody to class II antigens, and in some cases, antibody to its receptors. This absorption can be obtained from whole blood or from the plasma with leukocytes